with Michael Potchen, M.D.
|Professor of Radiology |
Director, Division of Diagnostic & Interventional Neuroradiology
Department of Imaging Sciences
University of Rochester Medical Center
Dana Foundation Grantee: 2011-2014
Your research team is
one of the only in the world using advanced brain imaging to tackle the
question of how malaria affects children’s brains, often leading to death and
neurologic disability. Why take on a condition like pediatric cerebral malaria?
Michael Potchen: Malaria is still a very active disease
worldwide, costing almost a million lives every year. Yet to date, there has
been almost no brain imaging of the disease in children. Until recently, we
didn’t understand why kids with cerebral malaria died;the underlying
pathophysiology behind the brain injuries sustained in survivors seems to be
mediated by different mechanisms. Although it’s been a significant disease for
a long time, too little is known about it.
village children in Zambia, where the Dana-funded study was conducted. Photo
courtesy of Michael Potchen.|
How has brain imaging
factored into this investigation?
MP: We’ve been involved in a longstanding study in Malawi,
in sub-Saharan Africa, to try to figure out the pathophysiology of cerebral
malaria, and several years ago they brought in an MRI scanner to do brain imaging
there. We published
findings in the New England Journal
of Medicine that edema (brain swelling) seems to be the primary cause of
death and morbidity. But we don’t know what’s causing the brain swelling. Before
we can treat the disease effectively, we need to know the cause.
In the latest study in Zambia, which the Dana Foundation
sponsored, we used a more powerful MRI with a higher-field magnet (1.5T vs .35T
in Malawi) to better understand what’s really going on in vivo and to try to get a better handle on the causes of edema.
What was your hypothesis
going into the study?
MP: We thought we would confirm some of the pathologic
findings found in autopsies that were done on the children in the Malawi study.
We weren’t sure if these findings were agonal in nature–i.e., they were there
because these kids died–or if they were part of the disease state that caused
the kids to die. That’s what we wanted to figure out in Zambia.
But you found something
MP: We did find something different. One of the pathophysiologic
hallmarks of cerebral malaria in autopsy findings is breakdown of the blood-brain
barrier, so that was a leading hypothesis for what was causing the brain to
swell. But we saw nothing on the imaging results to prove there was significant
breakdown of the blood-brain barrier. We did not confirm that hypothesis.
Our main finding was vascular congestion. That makes sense,
because the parasites actually live in the cerebral veins–that’s where they
hang out. They sequester, or concentrate there, and obstruct blood flow. Our
findings confirmed that venous obstruction is an etiology for the brain
swelling seen in cerebral malaria in children.
How has this work
contributed to moving the field of malaria research forward?
MP: It has moved the field forward significantly in the
sense that a lot of the focus in the past was on the breakdown of the
blood-brain barrier, and our findings disproved that as the only cause of brain
swelling. That in and of itself is a huge paradigm shift in the whole malaria
world. It’s the reason we’ve had a hard time getting this published–no one
wants to believe it. [laughs]
So your findings are
forcing a little reality check on what we thought we knew about malaria. How
might these insights affect clinical care?
MP: Now that we know some of these potential etiologies and
can rule out some of the others, we can try to address what’s going on with
these kids clinically. More studies need to be done to fully answer the
question of how clinical care will be affected, but one immediate implication
relates to treatment with corticosteroid drugs, which are used to reduce
swelling. Theoretically, steroids should work in these children, but they
don’t, and no one could figure out why not. Our finding that the blood-brain
barrier is intact explains why steroids don’t work to reduce edema.
We need to do more work to figure out what’s causing the
edema, and we need to study more children. At this point, we’ve scanned 16
children in our preliminary study with the high-field MRI, and we’re looking to
increase that number. Still, we have a pretty good idea what is happening, and
the types of therapy that might help based on the etiology. For example, many
of these kids have seizures, and it looks like seizures play a significant role
in the pathophysiology of brain injury in survivors. In the Dana-funded Zambian
study, we confirmed that some of the findings related to edema may also relate
to seizures. Clinically, this suggests that controlling seizures during the
acute phase of infection may decrease mortality, or at least reduce morbidity.
about this disease in children? Why not study adults?
MP: The big thing to understand is that this syndrome occurs
like this only in kids. Adults don’t get this. Kids who die of malaria die a
brain-stem death–they typically die of respiratory failure. Adults who die of
malaria die from multi-system failure: their liver goes out, their kidneys go
out. They go into coma due to kidney failure, not because their brain stem is
Even though the parasite also sequesters in the brains of
adults with malaria, it doesn’t have the same effect on the adult brain. It’s a
very important distinction.
Why only children? What’s different about their brains? No
one knows why kids get this and adults don’t. We think it has something to do
with autoregulation processes, which regulate blood flow in brain. Younger
brains react differently to congestion or blockages in the venous system.
Why has the
higher-strength MRI scanner been so important?
MP: The research the Dana
Foundation funded actually moved us forward quite a bit, because it allowed us
to use a higher-field magnet. That’s really the bottom line.
Because of the higher-field MRI, we were able to do
susceptibility-weighted imaging (SWI), an advanced imaging technique that can
detect micro-disturbances in the veins that the Malawi scanner missed. We were
looking for micro-hemorrhaging and intravascular hemozoin [a byproduct of
parasitic metabolism of hemoglobin] as evidence of where the parasite
sequesters in the brain. Autopsy results suggest it sequesters everywhere, but
it has not been known whether that is an agonal event or something that occurs
in vivo with everybody.
The SWI imaging enabled us to find out where the parasites
are living and whichere veins are involved. We now know they concentrate in the
veins of deep grey-matter structures such as the globus pallidus, the putamen,
and the caudate. Now we can backtrack into seeing what kind of edema is
associated with that pattern. That’s a big step.
What has been the
biggest challenge in this work?
MP: The biggest problem we have in this study is that I’m a
radiologist doing brain imaging in a field in which the malaria people, who are
infectious disease experts, don’t understand what we’re trying to do. The other
caveat is that people in the radiology world have no understanding of malaria. It’s
one of these situations where we fall right in the middle of two disciplines. The
radiology field and the malaria field are so disparate. When I present these
findings at a tropical disease conference, they have no idea what I’m talking
about. When I go to a radiology meeting, they have no idea what I’m talking
about. So it’s been tough to actually find someone qualified to review the
The reality is that the places where malaria is endemic are
low-income, limited-resource settings where people don’t have access to high
technology. As a general rule, they don’t have any way to use MRI to evaluate
malaria, which is why it’s never been studied. Malawi is a country of 17
million people and there is one radiologist; he’s the one who works with us. Zambia
is a country of 15 million with three radiologists.
Can this kind of effort
really make a difference in the long term, given the challenges of the local
health systems in malaria-endemic sub-Saharan Africa?
MP: This is one of those areas of science that is not all
black and white; there are huge parts of grey in the story, and that’s partly
because of the resource-poor setting in which we’re working. We’re really
grateful to the Dana Foundation for seeing that and helping to try to address it.
This study wasn’t just about understanding the disease, it
was also about building an infrastructure to sustain research in this environment.
That was a huge part of what we did with the Dana grant. We are continuing to
train radiologists and radiology techs, and were recently awarded an RO1 grant
from the NIH to continue this work. The goal is to continue to build on what we
have started to ensure a sustainable program where we can continue to scan.
technicians at the Cancer Diseases Hospital in Zambia, who worked with U.S.
researchers to administer the brain scans. The study helped build an
infrastructure for ongoing research in a resource-poor environment of
sub-Saharan Africa where malaria is endemic. Photo courtesy of Michael Potchen. |
We’re on the way, but we have a lot more work to do. In the
science world, people just don’t know what to make of these findings, but the
effect of malaria on children is a significant problem that we’re trying to
address. The Dana Foundation funding definitely helped us move forward in our
understanding of why these kids die and what we can do to help them.